1-Ethanamine-triazolo-benzodiazepines as diuretics

ABSTRACT

Triazolo-benzodiazepine-1-ethanamines of the formulas ##STR1## where R, R 1 , R 2 , R 3 , R 4  and Ring A are as defined in the specification, e.g., 8-chloro-N,N-dimethyl-β,6-diphenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine, and pharmacologically acceptable salts thereof, have been found to have substantial diuretic, natriuretic, but little, if any, kaliuretic activity, which can be used alone, or concomittently with other diuretic drugs such as furosemide or hydrochlorothiazide and/or with antihypertensive agents such as propranolo, captopril, minoxidil, prazosin, guanadrel sulfate, whose actions are supplemented by the action of a diuretic drug.

INTRODUCTION

This invention relates to pharmaceutical compositions and methods oftreating high blood pressure and other disease and abnormal conditionsin valuable warm-blooded animals, including humans, in need of diureticdrug treatment using certain novel or known4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamines. Thesecompounds have been found to possess diuretic and natriuretic (sodiumion removing) properties but little, if any, kaliuretic (potassium ionremoving) properties. Some of these compounds are new.

BACKGROUND OF THE INVENTION

In a variety of clinical (valuable warm-blooded animal and humantreatment) situations, the presence of too much extracellular fluid inbody tissues (edema) can be a problem in itself, or a problem whichinterferes with the treatment of other associated abnormal or diseaseconditions of concern to the patient and/or physician. Examples ofclinical circumstances that can be associated with edema includecongestive heart failure, advanced hepatic cirrohosis, nephroticsyndrome, and chronic renal failure.

Many diuretic drug compounds are known for treatment of edema and listsof various commercially available diuretics can be found in variouspublications, e.g., the Physicians' Desk Reference (PDR), 34th Edition(1980), published by Charles E. Baker, Jr., Copyright 1980 by LittonIndustries, Inc., Published by Medical Economics Company, a Littondivision at Oradell, NJ 07649, under DIURETICS on pp. 216-217 thereof.However, at least some of these known listed diuretic agents causeexcretion of substantial amounts of potassium ions necessitating thatcare is taken to avoid the urinary elimination of too much potassiumwhich is needed to maintain normal ion balance in the body.

In other clinical situations, blood pressure may be abnormally elevatedfor reasons known or unknown. Diuretic drug compounds, either because oftheir ability to remove extracellular fluid itself or because of someother pharmacological property, also frequently lower abnormallyelevated blood pressure.

Moreover, some compounds which initially show promise as diuretic drugsare often later dropped from consideration as diuretic drugs because oftoxicity or other undesired properties of the compounds.

Persons in the art concerned with the search for safe diuretic andnatriuretic drugs continue to look for drugs which will effectivelyremove water and sodium ion without also depleting the potassium ionlevels of the body to below acceptable levels.

OBJECTS OF THE INVENTION

It is an object of this invention to provide the medical, including theveterinary, profession with some diuretic drug compounds which helpalleviate high blood pressure (hypertension) and excess body fluidconditions (edema) and which diuretic drug compounds have little, ifany, effect on normal urinary potassium ion excretion rates.

It is another object of this invention to provide a process andpharmaceutical compositions for treating warm-blooded animals, includinghumans, suffering from high blood pressure (hypertension) and otherdisease or abnormal conditions, with diuretic drug compounds which arecomparatively safe as a class and which minimize the urine excretion ofpotassium ions from the body.

It is also an object of this invention to provide, as new compounds,some triazolo-benzodiazepine-1-ethanamine derivative compounds, whichare useful per se, or as their pharmacologically acceptable salts, asdiuretic drugs.

Other objects, aspects and purposes of this invention will be apparentfrom reading the remaining specification and the claims which follow.

SUMMARY OF THE INVENTION

Briefly, according to this invention we have discovered that a smallgroup of substituted triazolo-benzodiazepine-1-ethanamine compounds,e.g.,8-chloro-N,N-dimethyl-β,6-diphenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,and8-iodo-N,N-dimethyl-β,6-diphenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamineand their pharmacologically acceptable salts, are active diureticcompounds which assist warm-blooded animal patients, including humans,in excreting water and sodium ions while minimizing the amount ofpotassium ion excreted. As a class these triazolo-benzodiazepinecompounds possess little, if any, acute toxicity and they are compatiblein their concommitent use with other diuretic agents such as furosemideor hydrochlorothiazide, and with their concommitent use withantihypertensive drugs such as propranolol, captopril, minoxidil,prazosin, guanadrel sulfate, and the like, whose actions aresupplemented by the action of a diuretic drug.

DETAILED DESCRIPTION OF THE INVENTION

More particularly, this invention provides a process and pharmaceuticalcompositions for inducing diuresis in a warm-blooded animal patientwhich comprises administering to said patient a safe, non-toxic,effective amount of the compound of Formula I (See formulas below)wherein

R₃ is hydrogen or C₁ to C₃ -alkyl;

R₄ is phenyl or 1-, 3-, or 4-pyridinyl;

ring A is substituted by one or more fluorine, bromine, iodine, C₁ to C₃-alkyl, hydroxy, C₁ to C₃ -alkyloxy, C₁ to C₃ -alkylthio, amino, C₁ toC₃ -alkylamino, di(C₁ to C₃ -alkyl)amino, trifluoromethyl, or nitro;

or of a compound of the Formula II (See formulas below) wherein

R is phenyl substituted by zero to 2 methoxy or ortho-chlorine groups;

R₁ and R₂ are independently hydrogen or C₁ to C₃ -alkyl;

R₃ is hydrogen or C₁ to C₃ -alkyl;

R₄ is phenyl or 2-, 3-, or 4-pyridinyl;

ring A is substituted by one or more fluorine, chlorine, bromine,iodine, C₁ to C₃ -alkyl, hydroxy, C₁ to C₃ -alkyloxy, C₁ to C₃-alkylthio, amino, C₁ to C₃ -alkylamino, di(C₁ to C₃ -alkyl)amino,trifluoromethyl or nitro;

or a pharmaceutically acceptable salt thereof.

This invention also provides novel compounds of the Formula I (Seeformulas below) wherein

R₃ is hydrogen or C₁ to C₃ -alkyl;

R₄ is phenyl;

ring A is substituted by one or more iodine groups; or apharmaceutically acceptable salt thereof.

Examples of such compounds include:

8-iodo-N,N-dimethyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,

8-iodo-N,N,4-trimethyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,and

8,9-diiodo-N,N-dimethyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine.

The said novel compounds of this invention of the Formula I can beprepared by methods known in the art. For example,7-iodo-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-thione or its3-methyl derivative (prepared by methods known in the art) is reactedwith acetic acid hydrazide according to the method of Example 1 ofHester, Jr., U.S. Pat. No. 3,987,052. The resulting8-iodo-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine isreacted with a dimethylmethyleneammonium salt by the method of Hester,Jr., U.S. Pat. No. 4,075,221 to produce said novel compounds of thisinvention which are isolated and purified by conventional methods suchas extraction, column chromatography, crystallization and the like.Alternatively, the methods described in Hester, Jr., U.S. Pat. No.4,012,413 are used to produce the novel compounds of this invention ofthe Formula I.

This invention also provides novel compounds of the Formula II wherein

R is phenyl substituted by one to 2 substituents selected from the groupconsisting of methoxy in the meta or para position;

R₁ and R₂ are independently hydrogen or C₁ to C₃ -alkyl;

R₃ is hydrogen or C₁ to C₃ -alkyl;

R₄ is phenyl;

ring A is substituted by one or more fluorine, chlorine, bromine, C₁ toC₃ -alkyl, hydroxy, C₁ to C₃ -alkyloxy, C₁ to C₃ -alkylthio, amino, C₁to C₃ -alkylamino, di(C₁ to C₃ -alkyl)amino, trifluoromethyl or nitro;PS or a pharmaceutically acceptable salt thereof.

Examples of such compounds include:

8-chloro-β-(3-methoxyphenyl)-N,N-dimethyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,

8-chloro-β-(4-methoxyphenyl)-N,N-dimethyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,

8-chloro-β-(3-methoxyphenyl)-N-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,

8-chloro-β-(3-methoxyphenyl)-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,

8-bromo-β-(4-methoxyphenyl)-N,4-dimethyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,and

8-methylthio-β-(3-methoxyphenyl)-N,N-dimethyl-6-phenyl-4H-[1,24]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine.

This invention also provides novel compounds of the Formula II wherein

R is phenyl;

R₁ is hydrogen and R₂ is hydrogen or C₁ to C₃ -alkyl;

R₃ is hydrogen;

R₄ is phenyl;

ring A is substituted by one or more fluorine, chlorine, bromine, C₁ toC₃ -alkyl, hydroxy, C₁ to C₃ -alkyloxy, C₁ to C₃ -alkylthio, amino, C₁to C₃ -alkylamino, di(C₁ to C₃ -alkyl)amino, trifluoromethyl or nitro;

or a pharmaceutically acceptable salt thereof.

Examples of such compounds include:

8-chloro-β,6-diphenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,

8-chloro-N-methyl-β,6-diphenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,

8-bromo-β,6-diphenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,

8-trifluoromethyl-N-ethyl-β,6-diphenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,

8-nitro-β,6-diphenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,and

8-methyl-N-(1-propyl)-β,6-diphenyl-4H[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine.

This invention also provides novel compounds of the Formula II wherein

R is phenyl;

R₁ and R₂ are independently hydrogen or C₁ to C₃ -alkyl;

R₃ is C₁ to C₃ -alkyl;

R₄ is phenyl;

ring A is substituted by one or more fluorine, chlorine, bromine, C₁ toC₃ -alkyl, hydroxy, C₁ to C₃ -alkyloxy, C₁ to C₃ -alkylthio, amino, C₁to C₃ -alkylamino, di(C₁ to C₃ -alkyl)amino, trifluoromethyl or nitro;

or a pharmaceutically acceptable salt thereof.

Examples of such compounds include:

8-chloro-N,N,4-trimethyl-β,6-diphenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,

8-bromo-N,N,4-trimethyl-β,6-diphenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,

8-fluoro-N,4-dimethyl-β,6-diphenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,

8-methoxy-4-methyl-β,6-diphenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,

8-hydroxy-N,N,4-trimethyl-β,6-diphenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,

8-amino-N,N,4-trimethyl-β,6-diphenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine.

This invention also provides novel compounds of the Formula II wherein

R is phenyl;

R₁ and R₂ are independently hydrogen or C₁ to C₃ -alkyl;

R₃ is hydrogen or C₁ to C₃ -alkyl;

R₄ is phenyl;

ring A is substituted by one or more iodine groups; or apharmaceutically acceptable salt thereof.

Examples of such compounds include:

8-iodo-N,N-dimethyl-β,6-diphenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,

8-iodo-N-methyl-β,6-diphenyl4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,

8-iodo-β,6-diphenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine.

8-iodo-N,N,4-trimethyl-β,6-diphenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,

7,8-diiodo-N,N-dimethyl-β,6-diphenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,

8-iodo-N,4-dimethyl-β,6-diphenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine.

The novel compounds of this invention of the Formula II definedhereinabove are prepared by methods known in the art. For example, themethod of Hester, Jr., U.S. Pat. No. 4,075,221 is used to prepare thenovel compounds of the Formula II wherein R₁ and R₂ are C₁ to C₃ -alkyl.An appropriate1-(phenylmethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine is reactedwith a dialkylmethyleneammonium salt prepared either in advance or insitu by reacting an N,N,N',N'-tetraalkyldiaminomethane and a suitableacylating agent as described in Hester, Jr., U.S. Pat. No. 4,075,221,for example, acetyl chloride, to produce a novel compound of thisinvention of the Formula II. The requisite starting materials are knownin the art or are prepared by methods known in the art.

Compounds of the Formula II wherein one or both of R₁ and R₂ arehydrogen are prepared as follows. An appropriateN,N-dimethyl-β,6-diphenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamineis prepared by a method of Hester, Jr., U.S. Pat. No. 4,075,221 or byother known methods and converted to its quaternary ammonium compound byreaction with methyl iodide in a suitable solvent, for example,methanol. The resulting quaternary salt is reacted with ammonia or anappropriate alkylamine at from about 80° to 120° C. for up to 24 hours(in a pressure vessel if required) to produce the desired ethanaminecompound of this invention which is isolated and purified byconventional means.

Compounds of the Formulas I or II wherein R₃ is C₁ to C₃ -alkyl andcompounds of the Formula II wherein R is phenyl substituted by zero to 2methoxy or ortho-chlorine groups contain asymmetrically substitutedcarbon atoms and all enantiomers and diastereomers and mixtures thereofof such compounds are included within the scope of this invention.

Examples of acids suitable for making pharmaceutically acceptable acidaddition salts of the compounds of Formulas I or II for use according tothis invention include such acids as hydrogen chloride, hydrogenbromide, hydrogen iodide, sulfuric acid, orthophosphoric acid, aceticacid, lactic acid, citric acid, succinic acid, benzoic acid, salicyclicacid, pamoic aid, cyclohexanesulfonic acid, methanesulfonic acid, 1- and2-naphthalene sulfonic acids, p-toluenesulfonic acid, maleic acid,fumaric acid, and the like.

Dosage ranges for use of these compounds can vary from about 0.01 toabout 25 mg/kg of the patient's body weight depending upon the compoundbeing used and the extent of fluid loss desired. A general daily dosagerange of from about 0.5 to about 2000 mg in single or divided dosageunit forms given two to four times a day for an adult animal issuggested. A single adult human dose ranging from about 0.5 to about1000 mg can be used depending upon the condition being treated, the ageand weight of the patient, the compound being used, and similar factors.Preferred dosages for most applications are 0.5 to 5.0 mg per kg of bodyweight.

For treating some conditions such as hypokalemia associated withantihypertensive therapy, a physician may desire to prescribe the use ofone of these Formula I or II compounds for use in concommitentadministration with other diuretics such as hydrochlorothiazide,trichlormethiazide, furosemide, ethoxzolamide, chlorthalidone, and thelike, to minimize the loss of potassium from the patient's body. Forexample, for treating a hypokalemic condition, a physician might want toprescribe for a patient from 0.5 to 2000 mg/day of one of these FormulaI or II compounds, or a salt thereof, concommitent with 10 to 200 mg/dayof hydrochlorothiazide.

Also, in accordance with this invention, the Formula I or II compoundscan be used concommitently with the usual dosages of antihypertensivedrugs such as reserpine, deserpidine, hydralazine hydrochloride,mecamylamine hydrochloride, guanadrel sulfate, guanethedine sulfate,methyldopa, pentaerythritol tetranitrate, minoxidil, propranolol,captopril, prazosin, or the like.

The term "dosage unit form" as used in this specification and in theclaims refers to physically discrete units suitable as unitary dosagesfor mammalian subjects, each unit containing as the essential activeingredient a predetermined quantity of a compound of this invention withthe required pharmaceutical means which adapt said ingredient forsystemic administration. The specification for the novel dosage unitforms of this invention are dictated by and directly dependent on thephysical characteristics of the essential active ingredient and theparticular effect to be achieved in view of the limitations inherent inthe art of compounding such an essential active material for beneficialeffects in humans and animals, these being features of the presentinvention. Examples of suitable dosage unit forms in accordance withthis invention are tablets, capsules, orally administered liquidpreparations in suitable liquid vehicles, sterile preparations insuitable liquid vehicles for intramuscular and intravenousadministration, suppositories, and sterile dry preparations for theextemporaneous preparation of sterile injectable preparations in asuitable liquid vehicle. Suitable solid diluents or carriers for thesolid oral pharmaceutical dosage unit forms are selected from the groupconsisting of lipids, carbohydrates, proteins and mineral solids, forexample, starch, surcrose, lactose, kaolin, dicalcium phosphate,gelatin, acacia, corn syrup, corn starch, talc and the like. Capsules,both hard and soft, are filled with compositions of these ethanamineactive ingredients in combination with suitable diluents and excipients,for example, edible oils, talc, calcium carbonate and the like and alsocalcium stearate. Liquid preparations for oral administration areprepared in water or aqueous vehicles which advantageously containsuspending agents, for example, methylcellulose, acacia,polyvinylpyrrolidone, polyvinyl alcohol and the like. In the case ofinjectable forms, the injectable formulation must be sterile and must befluid to the extent that easy syringeability exists. Such preparationsmust be stable under the conditions of manufacture and storage, andordinarily contain in addition to the basic solvent or suspendingliquid, preservatives in the nature of bacteriostatic and fungistaticagents, for example, parabens, chlorobutanol, benzyl alcohol, phenol,thimerosal, and the like. In many cases, it is preferable to includeosmotically active agents, for example, sugars or sodium chloride inisotonic concentrations. Carriers and vehicles include vegetable oils,ethanol, polyols, for example glycerol, propylene glycol, liquidpolyethylene glycol, and the like. Any solid preparations for subsequentextemporaneous preparation of sterile injectable preparations aresterilized, preferably by exposure to a sterilizing gas, for example,ethylene oxide. The aforesaid carriers, vehicles, diluents, excipients,preservatives, isotonic agents and the like constitute thepharmaceutical means which adapt the preparations for systemicadministration.

The pharmaceutical dosage unit forms are prepared in accordance with thepreceding general description to provide from about 0.5 to about 1000 mgof the essential active ingredient per dosage unit form, which asaforesaid may be in the form of a semi-solid or solid, topical, oral orrectal preparation, a liquid oral preparation, an injectable preparationincluding liquid preparations and solid dry preparations forextemporaneous reconstitution to a liquid injectable preparation. Theamount of the essential active ingredient provided in the pharmaceuticaldosage unit forms is that amount sufficient to obtain diuretic effectsoften accompanied by antihypertensive effects within the aforesaideffective non-toxic range.

The useful pharmaceutical dosage unit forms of these compounds inpharmaceutical formulations are preferably adapted for systemicadministration to obtain diuretic effects comprising an effective,nontoxic amount of a compound according to Formula I or II or as itspharmacologically acceptable salt.

Examples of compounds of Formula I or II which can be used in thepractice of this invention include:

8-chloro-N,N-dimethyl-β,6-diphenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,

8-bromo-N,N-dimethyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,

8-bromo-N,N-dimethyl-β,6-diphenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,

8-chloro-β,6-diphenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,

N,N-dimethyl-8-(methylthio)-β,6-diphenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,

8-chloro-β-(3-methoxyphenyl)-N,N-dimethyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,

8-chloro-β-(2-chlorophenyl)-N,N-dimethyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,

8-chloro-N,N,4-trimethyl-β,6-diphenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,

8-chloro-N,N-dimethyl-β-(4-methoxyphenyl)-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,

8-iodo-N,N-dimethyl-β,6-diphenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,

8-chloro-N,N-dimethyl-β-(2-methoxyphenyl)-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,

8-bromo-N,N-dimethyl-6-(2-pyridinyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,and the like, or a pharmaceutically acceptable salt thereof.

Compounds of the Formula I, wherein R₄ is phenyl, and methods to preparethem, are disclosed in Hester, Jr., U.S. Pat. No. 3,759,943, and themethod of treating depression with such compounds is disclosed inHester, Jr., U.S. Pat. No. 3,969,504. Compounds of the Formula I,wherein R₄ is pyridinyl, and methods to prepare them, are disclosed inHester, Jr., U.S. Pat. No. 3,767,661. Some of the Formula II compoundsherein are known from Hester, Jr., U.S. Pat. No. 4,075,221 and areprepared by a method described therein.

Of these various compounds a lead compound with regard to diureticproperties is8-chloro-N,N-dimethyl-β,6-diphenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine.

The diuretic property of the Formula I or II compounds was determined byway of the following standard laboratory animal test.

TEST PROCEDURE AND RESULTS OF TEST FOR REPRESENTATIVE COMPOUNDS

The following standard laboratory animal test for diuretic activity oftest chemical compounds, compared against untreated control test animalsas well as against animals treated with commercially available standarddiuretic drug compounds was used to test compounds included within thescope of this invention.

PROCEDURE FOR DIURETIC SCREEN IN RATS WITH ORAL ADMINISTRATION OF TESTCOMPOUNDS Procedure of Test

Male TUC/SD (The Upjohn Company/Sprague Dawley) rats weighingapproximately 160 g are used for the diuretic screen. The rats aredeprived of food 24 hours prior to test time but have access to water adlib. until 11/2 hours before test time. From that point on andthroughout the test period both food and water are withheld. Tests areconducted in a temperature (75° F.) and humidity (48%) controlledlaboratory.

Tests are initiated by simultaneous hydration and oral administration oftest agents. This is accomplished by gavage with 25 ml/kg of normalsaline (0.9%) containing carboxymethylcellulose (0.5%) and the testcompounds (either dissolved or suspended). The rats are placed inmetabolism cages (2 rats/cage) and urine collected over the ensuing 5hours. Rats in 10 cages serve as controls, those in 2 cages receivehydrochlorothiazide (40 mg/kg) as the test standard and rats in theremaining cages (usually 44) receive test compounds. Each test compoundis given orally to 4 rats (2 cages) at a dose of 40 mg/kg.

Analysis of Test Results

Criteria for declaring test compounds "active" or "inactive" wereestablished as described by Roseberry and Gehan¹. Accordingly, testingis conducted in two stages:

Stage 1--A ratio, denoted (T/C)₁, of the mean urine volume of treated(test compound) and control rats is determined for each test compound.If (T/C)₁ is <1.66, the test compound is declared "inactive" If (T/C)₁is 1.66 or greater, the test compound is retested in Stage 2.

Stage 2--A ratio, denoted (T/C)₂, of the mean urine volume of treatedand control rats is determined for each retested compound and theproduct of the two ratios is calculated. If (T/C)₁.(T/C)₂ is <3.34, theretested compound is declared "inactive". If this product is 3.34 orgreater, the compound is declared "active".

The respective decision values for Stages 1 and 2 are determined fromcumulative data obtained in control and hydrochlorothiazide (teststandard) treated rats. These are subject to periodic reevaluation. Withthis two-stage procedure, the expected probability of a test compoundwith a true T/C of 2.25 being accepted is 0.99 while the probability ofa test compound with a true T/C of 1.5 being accepted is less than 0.01.

The following compounds were tested in the above test procedure to givethe data in the table which follows:

    ______________________________________                                        Compound Name                                                                 ______________________________________                                        1        8-Chloro-N,N--dimethyl-β,6-diphenyl-4H--                                 [1,2,4]triazolo[4,3-a][1,4]benzodiazepine-                                    1-ethanamine                                                         2        8-Bromo-N,N--dimethyl-6-phenyl-4H--[1,2,4]-                                   triazolo[4,3-a][1,4]benzodiazepine-1-                                         ethanamine, p-toluenesulfonate                                       3        8-Bromo-N,N--dimethyl-β,6-diphenyl-4H--[1,2,                             4]triazolo[4,3-a][1,4]benzodiazepine-1-                                       ethanamine                                                           4        8-Chloro-β,6-diphenyl-4H--[1,2,4]triazolo-                               [4,3-a][1,4]benzodiazepine-1-ethanamine,                                      monohydroiodide                                                      5        N,N--dimethyl-8-(methylthio)-β,6-diphenyl-                               4H--[1,2,4]triazolo[4,3-a][1,4]benzodiaze-                                    pine-1-ethanamine                                                    6        8-Chloro-β-(3-methoxyphenyl)-N,N--dimethyl-                              6-phenyl-4H--[1,2,4]triazolo[4,3-a][1,4]-                                     benzodiazepine-1-ethanamine                                          7        8-Chloro-β-(2-chlorophenyl)-N,N-- dimethyl-                              6-phenyl-4H--[1,2,4]-triazolo[4,3-a][1,4]-                                    benzodiazepine-1-ethanamine                                          8        8-Chloro-N,N,4-trimethyl-β,6-diphenyl-4H--                               [1,2,4]triazolo[4,3-a][1.4]benzodiazepine-                                    1-ethanamine                                                         9        8-Chloro-β-(4-methoxyphenyl)-N,N--dimethyl-                              6-phenyl-4H--[1,2,4]triazolo[4,3-a][1,4]-                                     benzodiazepine-1-ethanamine                                          10       8-Iodo-N,N--dimethyl-β,6-diphenyl-4H--[1,2,-                             4]triazolo[4,3-a][1,4]benzodiazepine-1-                                       ethanamine                                                           11       8-Chloro-β-(2-methoxyphenyl)-N,N--dimethyl-                              6-phenyl-4H--[1,2,4]triazolo[4,3-a][1,4]-                                     benzodiazepine-1-ethanamine                                          12       8-Bromo-N,N--dimethyl-6-(2-pyridinyl)-4H--                                    [1,2,4]triazolo[4,3-a][ 1,4]benzodiazepine-                                   1-ethanamine                                                         ______________________________________                                    

In the above described tests these twelve (12) compounds were rated"active" as diuretic drugs, based upon the following data:

    ______________________________________                                                Urine Volume Ratios                                                   Compound No.                                                                            T/C.sub.1 T/C.sub.2 T/C.sub.1 XT/C.sub.2 Value                      ______________________________________                                        1         2.51      2.10      5.27                                            2         2.63      2.98      7.84                                            3         2.18      2.17      4.73                                            4         2.34      2.53      5.92                                            5         2.88      2.29      6.60                                            6         2.3       3.18      7.31                                            7         2.26      1.67      3.77                                            8         2.31      3.05      7.05                                            9         2.77      2.00      5.57                                            10        3.26      2.88      9.44                                            11        2.69      1.87      5.03                                            12        1.75      1.98      3.47                                            ______________________________________                                    

These diuretic activity findings for this type of triazolobenzodiazepinecompounds are believed to be surprising and unexpected because someother closely related compounds either did not pass the first of the twoabove-described urine volume tests, or did not get a high enough ratingin the second urine volume test so that the multiplier value (3rd columnvalue) was high enough to rate the compound as "active" in this standardlaboratory animal diuretic test. Compounds which were rated inactive inthese diuretic tests include:

    ______________________________________                                        (A)     8-chloro-1-[2-(diethylamino)ethyl]-6-phenyl-                                  4H--[1,2,4]triazolo[4,3-a][1.4]benzodiazepine                         (B)     8-chloro-1-(2-aminoethyl)-6-phenyl-4H--                                       [1,2,4]triazolo[4,3-a][1,4]benzodiazepine                             (C)     1-[2-(N,N--dimethylamino)ethyl]-6-phenyl-4H--                                 [1,2,4]triazolo[4,3-a][1,4]benzodiazepine                             (D)     1-(2-aminoethyl)-6-phenyl-4H--[1,2,4]triazolo-                                [4,3-a][1,4]benzodiazepine                                            (E)     1-[2-(N,N--dimethylamino)ethyl]-6-(2-chloro-                                  phenyl)-4H--[1,2,4]triazolo[4,3-a][1,4]benzo-                                 diazepine                                                             (F)     8-bromo-1-(2-aminoethyl)-6-phenyl-4H--[1,2,4]-                                triazolo[4,3-a][1,4]benzodiazepine                                    (G)     N,N--dimethyl-β,6-diphenyl-4H--[1,2,4]triazolo-                          [4,3-a][1,4]benzodiazepine-1-ethanamine                               (H)     8-chloro-N,N--dimethyl-β-phenyl-6-(2-chloro-                             phenyl)-4H--[1,2,4]triazolo[4,3-a][1,4]benzo-                                 diazepine-1-ethanamine                                                ______________________________________                                    

In this specification and in the detailed examples which follow thefollowing abbreviations have the indicated meaning. N₂ means nitrogengas; DMF means N,N-dimethylformamide; mmole means millimole; NaHCO₃means sodium bicarbonate; CH₂ Cl₂ means methylene chloride; Na₂ SO₄means anhydrous sodium sulfate; THF means tetrahydrofuran; H₂ O meanswater; NaCl means sodium chloride; brine means a saturated aqueous NaClsolution; EtOAc means ethyl acetate; Skelly B (or Skellysolve B) is atradename for a solvent of essentially n-hexane, bp 60°-68° C. (MerckIndex, Ninth Edition (1976) page 1106); hr means hour or hours; minmeans minutes; MeOH means absolute methanol; EtOH means absoluteethanol; IR means infra-red spectrum and analysis; UV means ultravioletspectrum and analysis; NMR means nuclear magnetic resonance spectrum andanalysis; MS means mass spectrum and analysis; Anal means analysis; P₂S₅ means phosphorous pentasulfide; HCl means hydrogen chloride; Et₂ Omeans diethyl ether; pet. ether means light petroleum ether of bp about35°-37° C.; NaOH means sodium hydroxide; TLC means thin layerchromatography procedures; butanol generally means n-butanol.

EXAMPLE 18-Chloro-β,6-diphenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,and its monohydriodide salt

A. Quaternary SaltPreparation--2-(8-Chloro-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-yl)-N,N,N-trimethyl-2-phenylethanaminiumiodide

To an ice-cooled, nitrogen gas covered solution of 10.0 g (22.6 mmol) of8-chloro-N,N-dimethyl-β,6-diphenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine(See Example 10 of U.S. Pat. No. 4,075,221) in 175 ml of methanol, therewas added 16.90 ml (38.54 g, 0.272 mol) of methyl iodide over 18minutes. The solution was stirred at room temperature for 6.5 hoursduring which time a solid crystallized. The suspended solid wascollected on a filter, washed with a small amount of methanol and driedto yield 9.82 g (68.1% yield) of the titled quaternary ammonium iodidesalt, m.p. 216°-217° C. (dec.), containing some methanol solvation. Thefiltrate from the filtration step was combined and concentrated in vacuoto obtain a crude solid residue, which residue was recrystallized frommethanol to yield 3.28 g (22.7%) of the subtitled quaternary ammoniumiodide salt, m.p. 214°-215° C. (dec.) and 0.48 g (3.3% yield) of anothercrop of the subtitled quaternary ammonium iodide salt, m.p. 212°-214° C.(dec.). An analytical sample of this material was recrystallized frommethanol to give the subtitled quaternary ammonium iodide salt, m.p.217°-218° C., which analyzed as follows:

Anal. Calcd. for C₂₇ H₂₇ N₅ ClI: C, 55.55; H, 4.66; N, 12.00%. Found(anal. corrected for 9.03% MeOH): C, 56.13; H, 4.34; N, 12.54%.

B.8-Chloro-β,6-diphenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,characterized as its monohydriodide salt

A mixture of 4.0 g (6.85 mmol) of the quaternary ammonium salt from PartA above and 200 ml of freshly distilled ammonia was sealed in a pressurereaction vessel and heated in an oil bath at 100° C. under 650 psig for18 hours and then allowed to cool. The reaction mixture was removed fromthe pressure vessel and concentrated under a stream of nitrogen. Theresidue was treated with 400 ml of a 1:1 v/v mixture of ethyl acetateand methylene dichloride. A solid (A) which was suspended in the mixturewas collected on a filter and the filtrate was concentrated to 1/3 ofits volume. An additional solid (B) came out of this concentratedfiltrate and was similarly separated by filtration. Solid (B) wassuspended and crystallized from acetonitrile to yield 0.50 g (13.5%yield) of the tilted amine as its hydriodide, m.p. 257°-259° C. and 0.11g (3.0% yield) of the same amine hydriodide salt, m.p. 265.5°-267° C.solvated with acetonitrile.

Solid A was also crystallized from acetonitrile to yield 1.10 g (29.6%yield) of the titled amine as its hydriodide, m.p. 270°-273° C. and 0.18g (4.8% yield) of the same amine hydriodide salt, m.p. 270°-273° C. freeof acetonitrile.

Anal. Calcd. for C₂₄ H₂₀ N₅ Cl.HI: C, 53.20; H, 3.90; N, 12.93; Cl,6.55%. Found: C, 53.01; H, 3.88; N, 13.24; Cl, 6.54%.

This amine salt can be converted, if desired, to its tilted free amineform by treating the amine hydriodide salt with aqueous sodiumbicarbonate solution, according to known chemical procedures.

EXAMPLE 2 General procedure for the preparation ofβ,6-diaryl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamines ofthe Formula II wherein R₁ and R₂ are C₁ to C₃ -alkyl

To an ice cooled N₂ covered mixture of 2.0 mmole of the1-(phenylmethyl)triazolobenzodiazepine, 2.2 mmole ofN,N,N',N'-tetraalkyldiaminomethane in 15 ml of DMF was added 2.3 mmoleof acetyl chloride dropwise. The reaction was stirred for from 3-5 hoursat about 0° to 10° C. If not complete an additional 0.1-0.5 mmole ofacetyl chloride was added and stirring was continued for up to a totalof 24 hours. When complete the reaction was poured into a mixture ofice:aqueous NaHCO₃. The mixture was extracted with CH₂ Cl₂ and theorganic layer was washed with dilute brine, dried over Na₂ SO₄ andconcentrated in vacuo. Chromatography of the residue over silica geleluting with methanol and/or recrystallization from ethyl acetate orfrom diethyl ether-light petroleum ether (bp 35°-37° C.) yielded theproduct.

EXAMPLE 38-Chloro-β-(4-methoxyphenyl)-N,N-dimethyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine

A. General procedure for the preparation of 1-(Phenylmethyl)intermediates as exemplified by the preparation of8-chloro-1-(4-methoxyphenylmethyl)-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

A mechanically stirred solution of 4-methoxyphenylacetic acid (1.66 g,0.01 mole) in THF (30 ml), under N₂, was cooled in an ice bath andtreated with carbonyl diimidazole (CDI). After 1 hour7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine (2.56 g, 0.009 mole)was added and the reaction was allowed to continue until a precipitatebegan to form (usually in approximately 4-6 hours), at which time theice bath was removed and the reaction allowed to stir at ambienttemperature for 16 hours. The precipitate was filtered, washed with THFand dried in the vacuo oven overnight. In experiments where thisprecipitate appeared to be slightly soluble in THF, the filtrate wasconcentrated in vacuo and the residue mixed with CH₂ Cl₂ and H₂ O. TheCH₂ Cl₂ solution was washed with brine, dried over Na₂ SO₄ andconcentrated in vacuo to yield additional product.

A stirred mixture of the above product in aetic acid (50 ml) wasrefluxed, under N₂, for 2-3 hours then concentrated in vacuo. Theresidue was mixed with CH₂ Cl₂ and H₂ O. The Ch₂ Cl₂ was washed withaqueous NaHCO₃ and brine, dried over Na₂ SO₄ and concentrated in vacuo.This material was crystallized from EtOAc-Skelly B to give a 54.8% yieldof the subtitled intermediate, mp 183° C. The analytical sample had aC:H:N:Cl ratio of 69.60:4.68: 13.73:8.62. Calculated for C₂₄ H₁₉ N₄ ClO:69.47:4.62:13.50:8.55.

B.8-Chloro-N,N-dimethyl-β-(4-methoxyphenyl)-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine

A stirred solution of the compound from Part A above (2.0 g, 0.005 ml)in DMF (25 ml) was cooled in an ice bath, treated withN,N,N',N'-tetramethyldiaminomethane (0.819 ml, 0.006 mol) and thendropwise with acetyl chloride (0.5 ml, 0.00704 mol). The mixture waskept in the ice bath for 5 hours 15 minutes and poured into a mixture ofice and saturated NaHCO₃. The mixture was extracted with CH₂ Cl₂ ; theextract was washed with dilute NaCl, dried (Na₂ SO₄) and concentrated invacuo using xylene to help remove last traces of DMF. The residue waschromatographed on silica gel with MeOH. The product thus obtained wascrystallized from EtOAc-Skelly B to give: 1.38 g, mp 138.5°-145° and0.26 g, mp 137.5°-142.5° of the titled product. The analytical samplehad mp 136°-142°. The structure was supported by IR, UV, NMR and MS.

Anal. calcd. for C₂₇ H₂₆ ClN₅ O: C, 68.71; H, 5.55; Cl, 7.51; N, 14.84.Found: C, 68.41; H, 5.79; Cl, 7.45; N, 14.68; H₂ O, 0.64.

EXAMPLE 48-Chloro-β-(3-methoxyphenyl)-N,N-dimethyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine

A.8-Chloro-1-(3-methoxyphenylmethyl)-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

A mechanically stirred solution of 3-methoxyphenylacetic acid (1.66 g,0.01 mol) in THF (30 ml), under N₂, was cooled in an ice bath andtreated with carbonyl diimidazole (CDI). After one hour7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine (2.56 g, 0.009 mol)was added and the reaction was allowed to continue until a precipitatebegan to form (usually in approximately 4-6 hours), at which time theice bath was removed and the reaction allowed to stir at ambienttemperature for 16 hours. The precipitate was filtered, washed with THFand dried in the vacuum oven overnight. In experiments where thisprecipitate appeared to be slightly soluble in THF, the filtrate wasconcentrated in vacuo and the residue mixed with CH₂ Cl₂ and H₂ O. TheCH₂ Cl₂ solution was washed with brine, dried over Na₂ SO₄ andconcentrated in vacuo to yield additional product.

A stirred mixture of the above product in acetic acid (50 ml) wasrefluxed, under N₂, for 2-3 hours then concentrated in vacuo. Theresidue was mixed with Ch₂ Cl₂ and H₂ O. The CH₂ Cl₂ was washed withaqueous NaHCO₃ and brine, dried over Na₂ SO₄ and concentrated in vacuo.This material was crystallized from EtOAc-Skelly B to give 1.08 g, mp133°-134° and 0.56 g, mp 135°-137° of the subtitled intermediate. Theanalytical sample had mp 132°-135° and a C:H:N:Cl ratio of69.09:4.60:13.52:8.52. Calculated for C₂₄ H₁₉ N₄ ClO:69.47:4.62:13.50:8.55.

B.8-Chloro-β-(3-methoxyphenyl)-N,N-dimethyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1ethanamine

To an ice cooled N₂ covered mixture of 2.0 mmole of the compound fromPart A above, 2.2 mmole of N,N,N',N'-tetramethyldiaminomethane in 15 mlof DMF was added 2.3 mmole of acetyl chloride dropwise. The reaction wasstirred for from 3-5 hours at 4° C. An additional 0.1-0.5 mmole ofacetyl chloride was added and stirring was continued for a total of 16hours. When complete the reaction was poured into a mixture ofice:aqueous NaHCO₃. The mixture was extracted with Ch₂ Cl₂ and theorganic layer was washed with dilute brine, dried over Na₂ SO₄ andconcentrated in vacuo. Chromatography of the residue over silica geleluting with methanol and recrystallization from diethyl ether-petroleumether yielded the titled product, mp 139°-140°, which had a C:H:N:Clratio of 68.30:5.76:14.79:7.63. Calculated for C₂₇ H₂₆ ClN₅ O:68.71:5.55:14.84:7.51.

EXAMPLE 58-Chloro-N,N-4-trimethyl-β,6-diphenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine

A. 7-Chloro-1,3-dihydro-3-methyl-5-phenyl-2H-1,4-benzodiazepine-2-thione

A stirred mixture of7-chloro-1,3-dihydro-3-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (10 g,0.035 mol) in pyridine (300 ml), treated with P₂ S₅ (8.0 g, 0.036 mmol)was refluxed, under N₂, for 2 hours then concentrated in vacuo. Toremove the remaining pyridine the residue was combined with toluenetwice with concentration after each addition. The remaining material wasmixed with cold NaHCO₃ and extracted twice with CH₂ Cl₂. At this point aprecipitate thought to be undissolved product formed between the twolayers. This was filtered and washed with CH₂ Cl₂ and H₂ O. The NaHCO₃layer was extracted with CH₂ Cl₂ again. The combined CH₂ Cl₂ extractswere washed with brine, dried over Na₂ SO₄, and concentrated in vacuo.The residue was crystallized from EtOAc-Skelly B to give 3.0 g of thesubtitled intermediate, mp 250°. The precipitate was also recrystallizedfrom EtOAc-Skelly B to give 3.01 g of additional subtitled intermediate,mp 255°.

B.8-Chloro-4-methyl-1-phenylmethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

A stirred mixture of7-chloro-1,3-dihydro-3-methyl-5-phenyl-2H-1,4-benzodiazepine-2-thione(3.0 g, 0.01 mol), phenyl acetic acid hydrazide (4.95 g, 0.033 mol) andbutanol (150 ml) was refluxed for 16 hours while N₂ was being bubbledthrough the mixture. The reaction mixture was concentrated under highvacuum, and the residue mixed with iced H₂ O. The product was filteredand dissolved in CH₂ Cl₂. The CH₂ Cl₂ was washed with dilute HCl andbrine, dried over Na₂ SO₄ and concentrated in vacuo. At this point itappeared that complete cyclization had not been achieved. Therefore, theresidue was combined with acetic acid (100 ml) and refluxed for 2 hoursunder N₂. The reaction mixture was concentrated in vacuo and the residuemixed with CH₂ Cl₂ and H₂ O. The CH₂ Cl₂ was washed with NaHCO₃ andbrine, dried over Na₂ SO₄ and concentrated in vacuo. The material wascrystallized from EtOAc-Skelly B to give 1.55 g, mp 195°-197° of thesubtitled intermediate, which had a C:H:N:Cl ratio of72.38:4.85:14.16:8.81. Calculated for C₂₄ H₁₉ N₄ Cl:72.26:4.80:14.05:8.89.

C.8-Chloro-N,N,4-trimethyl-β,6-diphenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine

A stirred solution of the compound from Part B above (3.0 g, 0.0075 mol)in DMF (80 ml) was cooled in an ice bath under N₂ and treated withN,N,N',N'-tetramethyldiaminomethane (1.32 ml, 0.0097 mol) and thendropwise with acetyl chloride (0.74 ml, 0.0104 mol). The mixture waskept in the ice bath for 18 hours and poured into a mixture of ice andsaturated NaHCO₃. This mixture was extracted with CH₂ Cl₂. The extractwas washed with brine, dried (Na₂ SO₄) and concentrated in vacuo usingxylene to help remove residual DMF. The residue was crystallized fromEt₂ O-petroleum ether to give 2.4 g of the titled compound, mp200°-103°. The analytical sample was recrystallized from EtOAc and hadmp 204°-205°. The structure was supported by IR, UV, NMR and MS.

Anal. calcd. for C₂₇ H₂₆ ClN₅ : C, 71.11; H, 5.75; Cl, 7.78; N, 15.36.Found: C, 70.78; H, 5.79; Cl, 7.79; N, 15.27.

EXAMPLE 6 8-Iodo-N,N-dimethyl-β,6-diphenyl-4H-[1,2,4]triazolo[4,3-a][1,4benzodiazepine-1-ethanamine

A. 1,3-Dihydro-7-iodo-5-phenyl-2H-1,4-benzodiazepin-2-one

Bromoacetyl bromide (50.06 g, 0.248 mol) was added dropwise to a stirredsolution of 2-amino-5-iodobenzophenone (40.0 g, 0.124 mol) in toluene(800 ml), under N₂. After the addition was complete the reaction mixturewas heated to 800° C. for 4 hours. The mixture was allowed to cool toambient temperature and then treated with 20% NaOH (500 ml); it wasstirred for 15 minutes and the layers were separated. The aqueous layerwas extracted with CH₂ Cl₂. The organic layers were combined, washedwith brine, dried (Na₂ SO₄) and concentrated in vacuo. The residue wascrystallized from MeOH to yield 38.22 g (69.42%), mp 124°-125° and 9.66g (17.54%), mp 125°-126° of the α-bromoacetamide intermediate.

Ammonia (2150 ml) was condensed into a flask fitted with a cold fingercondenser, and a mechanical stirrer with the reaction vessel immersed ina dry ice acetone bath. The α-bromoacetamide (40 g, 0.09 mol) obtainedabove was then added and the dry ice bath removed allowing the reactionmixture to reflux. After 2 hours the ammonia was allowed to evaporateunder a slow stream of N₂. The residue was combined with CH₂ Cl₂ (450ml) and H₂ O (250 ml) and stirred for 15 minutes. The layers wereseparated and the aqueous layer was extracted with CH₂ Cl₂. The combinedorganic extracts were dried (Na₂ SO₄) and concentrated. The resultingresidue was combined with EtOH (500 ml) and heated to reflux withportions of EtOH being distilled off and replaced with fresh EtOHperiodically during the reaction. After 21/2 hours the reaction mixturewas decolorized, partially concentrated in vacuo and allowed tocrystallize yielding 20.67 g (63.4%) of the subtitled intermediate, mp223°-225°. Further concentration yielded an additional 5.64 g (17.3%) mp220°-222° of the subtitled intermediate. The product was one spot by TLC(2% MeOH:CH₂ Cl₂). The analytical sample was recrystallized from EtOHand had mp 223°-225°. The structure was supported by IR, UV, NMR, andMS.

Analysis Calc'd for C₁₃ H₁₁ IN₂ O: C, 49.74; H, 3.06; I, 35.04; N, 7.74.Found: C, 50.14; H, 3.31; I, 34.86; N, 7.76.

B. 1,3-Dihydro-7-iodo-5-phenyl-2H-1,4-benzodiazepine-2-thione

A stirred mixture of phosphorus pentasulfide (1.2 g, 0.0054 mol) andpyridine (50 ml) was placed in a preheated oil bath (130° C.), under N₂.After the phosphorus pentasulfide had dissolved, the amide from Part Aabove (2.0 g, 0.0055 mol) was added and the mixture quickly heated toreflux. After refluxing 45 minutes the reaction mixture was cooled in anice bath and concentrated in vacuo. The residue was combined with asmall amount of CH₂ Cl₂ and ice cold aqueous NaHCO₃ (50 ml) and stirredin an ice bath for 45 minutes. The resulting suspension was filtered andthe solid was washed with CH₂ Cl₂ and H₂ O and dried in vacuo to yield1.53 g of the subtitled intermediate, mp 248°-250°. This product wasfound to be one spot on TLC (2% MeOH:CH₂ Cl₂). The structure wassupported by NMR. In an attempt to retrieve more product the filtratewas separated into its respective layers and the aqueous layer extractedwith CH₂ Cl₂. The pooled organic extracts were washed with brine, dried(Na₂ SO₄) and concentrated in vacuo. The residue was suspended in asmall amount of CH₂ Cl₂ and filtered to yield 0.20 g, mp 237°-238°,which was found to be impure product by TLC.

In subsequent runs it was found that the P₂ S₅ complex generated in thisreaction was difficult to decompose. Useful product was obtained bystirring the crude product with saturated NaHCO₃ and a large volume ofCH₂ Cl₂. When the solid had dissolved the CH₂ Cl₂ solution was washed(dilute NaCl), dried (Na₂ SO₄), concentrated to a small volume, dilutedwith EtOH and crystallized to give the subtitled intermediate, mp238.5°-239.5° (dec.).

C.8-Iodo-6-phenyl-1-(phenylmethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

A stirred mixture of7-iodo-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-thione (3.78 g, 0.01mol), phenylacetic acid hydrazide (4.5 g, 0.03 mol) and butanol (150 ml)was heated to reflux while N₂ was bubbled through the mixture. Afterrefluxing 17 hours the reaction mixture was concentrated under vacuum.The residue was combined with ice water and allowed to stir for a fewminutes. The resulting suspension was filtered and the filtered materialwashed with CH₂ Cl₂. The filtrate was separated into its respectivelayers and the aqueous layer washed with CH₂ Cl₂. The combined organicfractions were washed with brine, dried (Na₂ SO₄) and concentrated invacuo. The residue was triturated with EtOAc to yield 1.43 g (30.04%),mp 200°-201° of the subtitled intermediate. The analytical sample wasrecrystallized from EtOAc and had mp 201°-202°. The IR, NMR and massspectra supported the proposed structure.

Anal. Calc'd for C₂₃ H₁₇ N₄ I: C, 58.00; H, 3.60; N, 11.76; I, 26.64.Found: C, 57.74; H, 3.55; N, 11.64; I, 26.39.

D.8-Iodo-N,N-dimethyl-β,6-diphenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine

A stirred solution of the compound from Part C above (0.953 g, 0.002mol) in DMF (14 ml) was cooled, under N₂, in an ice bath and treatedwith N,N,N',N'-tetramethyldiaminomethane (0.328 ml, 0.0024 mol) and thendropwise with acetyl chloride (0.2 ml, 0.0028 mol). A light precipitateformed that became heavier as the reaction progressed. The mixture waskept in the ice bath for 8 hours 10 minutes and then poured into amixture of ice and saturated NaHCO₃. This was extracted with CH₂ Cl₂.The extract was washed with dilute NaCl, dried (Na₂ SO₄) andconcentrated in vacuo using xylene to help remove residual DMF. Theresidue was chromatographed on silica gel with MeOH. The pure productthus obtained was crystallized from Et₂ O-petroleum ether to give 0.284g, mp 192.5°-193.5°, and 0.033 g, mp 192°-193°, of the title product.Early fractions from this column contained a mixture of recoveredstarting material and product. This was rechromatographed on silica gelwith 10% MeOH-CHCl₃. The product obtained from this column wascrystallized from EtOAc-Skelly B to give 0.248 g, mp 194°-195.5°, and0.064 g, mp 192.5°-194° of additional titled product. The analyticalsample was recrystallized from EtOAc-Skelly B and had mp 194°-196°. Thestructure was supported by IR, UV, NMR, and MS.

Anal. Calc'd for C₂₆ H₂₄ N₅ I: C, 58.55; H 4.53; I, 23.79; N, 13.13.Found: C, 58.17; H, 4.50; I, 22.75, 24.03; N, 13.39.

EXAMPLE 7 General procedure for the preparation ofβ,6-Diaryl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamines ofthe Formula II wherein one or both of R₁ and R₂ are hydrogen

A mixture of 3.5 mmole of the amine quaternary salt and an excess of theappropriate amine was reacted under N₂ in an oil bath at about 80° to120° C. for up to 24 hours and allowed to cool.

Work-up 1: The reaction mixture was poured into ice:saturated aqueousNaHCO₃. If crystalline the solid was filtered, if not the mixture wasextracted with CH₂ Cl₂ and the extract was washed with dilute brine,dried over Na₂ SO₄ and concentrated in vacuo.

Work-up 2: The excess amine was removed by distillation and the residuedissolved in CH₂ Cl₂ or EtOAc, washed with aqueous NaHCO₃ and dilutebrine, dried over Na₂ SO₄ and concentrated in vacuo.

The residue was either chromatographed over silica gel, eluting withmethanol or methanol-methylene chloride mixtures and/or recrystallizedfrom ethyl acetate, methanol, ethanol-ethyl acetate, diethyl ether-lightpetroleum ether, or the like, to yield the product. Example 1hereinabove exemplifies this procedure.

EXAMPLE 88-Chloro-N-methyl-β,6-diphenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine

A mixture of the quaternary ammonium salt from Example 1, Part A,hereinabove (7 mmole) and 50 ml of methylamine is sealed in a pressurereaction vessel and heated in an oil bath at 100° for 24 hours and thenallowed to cool. The reaction mixture is removed from the pressurevessel and concentrated under a stream of nitrogen. The residue istreated with a 1:1 (v/v) mixture of ethyl acetate and methylenedichloride. Concentration of this mixture gives the titled product whichis further purified by recrystallization.

EXAMPLE 98-Iodo-N,N-dimethyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine

The iodothione prepared as described in Example 6, Part B, hereinaboveis reacted with acetic aid hydrazide by the method described in Example1 of Hester, Jr., U.S. Pat. No. 3,987,052 to produce8-iodo-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine.

A stirred solution of the intermediate thus produced (0.01 mole) in dryDMF (50 ml) is cooled in an ice bath under nitrogen and treatedsuccessively with N,N,N',N'-tetramethyldiaminomethane (0.012 mole) anddropwise with acetyl chloride (0.013 mole). The cooling is maintainedfor two hours, and the mixture is then poured into a mixture of ice andsaturated sodium bicarbonate. The mixture is saturated with sodiumchloride and extracted with chloroform. The extracts are washed withbrine, dried over anhydrous sodium sulfate and concentrated to removethe solvent using xylene and toluene to help remove the residual DMF togive the titled product, which is further purified by conversion to acrystalline acid addition salt.

EXAMPLE 10

Ten thousand hard gelatin capsules for oral use, each containing 25 mgof8-chloro-N,N-dimethyl-β,6-diphenyl-4H-[1,2,4]triazolo-[4,3-a][1,4]benzodiazepine-1-ethanamineand 2.5 mg of minoxidil are prepared from the following ingredients:

    ______________________________________                                                             Gm.                                                      ______________________________________                                        8-chloro-N,N--dimethyl-β,6-diphenyl-                                                            250                                                    4H--[1,2,4]-triazolo[4,3-a][1,4]-                                             benzodiazepine-1-ethanamine                                                   Minoxidil               25                                                    Starch                 350                                                    Talc                   250                                                    Calcium stearate       150                                                    Lactose                1750                                                   ______________________________________                                    

One capsule one to four times a day is useful in the treatment ofhypertension.

EXAMPLE 11

Ten thousand tablets for oral use, each containing 25 mg of8-iodo-N,N-dimethyl-β,6-diphenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamineare prepared from the following ingredients:

    ______________________________________                                                          Gm.                                                         ______________________________________                                        8-iodo-N,N--dimethyl-β,6-di-                                                                 250                                                       phenyl-4H--[1,2,4]triazolo-                                                   [4,3-a][1,4]benzodiazepine-                                                   1-ethanamine                                                                  Lactose             1200                                                      Corn starch         500                                                       Talc                500                                                       Calcium stearate     25                                                       ______________________________________                                    

The powdered ingredients are thoroughly mixed and slugged. The slugs arebroken into granules which are then compressed into tablets. To inducediuresis in adult humans, one tablet is administered one to four timesdaily.

FORMULAS ##STR2##

We claim:
 1. A process for inducing diuresis in a warm-blooded animalpatient which comprises administering to such patient a safe, non-toxic,effective amount of a compound of the Formula Iwherein R₃ is hydrogen orC₁ to C₃ -alkyl; R₄ is phenyl or 2-, 3-, or 4-pyridinyl; ring A issubstituted by one or more fluorine, bromine, iodine, C₁ to C₃ -alkyl,hydroxy, C₁ to C₃ -alkyloxy, C₁ to C₃ -alkylthio, amino, C₁ to C₃-alkylamino, di(C₁ to C₃ -alkyl)amino, trifluoromethyl, or nitro;or of acompound of the Formula II ##STR3## wherein R is phenyl substituted byzero to two methoxy or orthochlorine groups; R₁ and R₂ are independentlyhydrogen or C₁ to C₃ -alkyl; R₃ is hydrogen or C₁ to C₃ -alkyl; R₄ isphenyl or 2-, 3-, or 4-pyridinyl; ring A is substituted by one or morefluorine, chlorine, bromine, iodine, C₁ to C₃ -alkyl, hydroxy, C₁ to C₃-alkyloxy, C₁ to C₃ -alkylthio, amino, C₁ to C₃ -alkylamino, di(C₁ to C₃-alkyl)amino, trifluoromethyl, or nitro;or a pharmaceutically acceptablesalt thereof.
 2. A process according to claim 1 wherein said patient istreated with8-chloro-N,N-dimethyl-β,6-diphenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethaneamine,or a pharmaceutically acceptable salt thereof.
 3. A process according toclaim 1 wherein said patient is treated with8-bromo-N,N-dimethyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,or a pharmaceutically acceptable salt thereof.
 4. A process according toclaim 1 wherein said patient is treated with8-bromo-N,N-dimethyl-β,6-diphenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,or a pharmaceutically acceptable salt thereof.
 5. A process according toclaim 1 wherein said patient is treated with8-chloro-β,6-diphenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,or a pharmaceutically acceptable salt thereof.
 6. A process according toclaim 1 wherein said patient is treated withN,N-dimethyl-8-(methylthio)-β,6-diphenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,or a pharmaceutically acceptable salt thereof.
 7. A process according toclaim 1 wherein said patient is treated with8-chloro-β-(3-methoxyphenyl)-N,N-dimethyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,or a pharmacologically acceptable salt thereof.
 8. A process accordingto claim 1 wherein said patient is treated with8-chloro-β-(2-chlorophenyl)-N,N-dimethyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,or a pharmacologically acceptable salt thereof.
 9. A process accordingto claim 1 wherein said patient is treated with8-chloro-N,N,4-trimethyl-β,6-diphenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,or a pharmacologically acceptable salt thereof.
 10. A process accordingto claim 1 wherein said patient is treated with 8-chloro-β-(4-methoxyphenyl)-N,N-dimethyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,or a pharmacologically acceptable salt thereof.
 11. A process accordingto claim 1 wherein said patient is treated with8-iodo-N,N-dimethyl-β-6-diphenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,or a pharmacologically acceptable salt thereof.
 12. A process accordingto claim 1 wherein said patient is treated with8-chloro-β-(2-methoxyphenyl)-N,N-dimethyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,or a pharmacologically acceptable salt thereof.
 13. A process accordingto claim 1 wherein said patient is treated with8-bromo-N,N-dimethyl-6-(2-pyridinyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,or a pharmacologically acceptable salt thereof.
 14. A method fortreating hypertension in a warm-blooded animal patient which comprisesconcomittantly administering to said patient an amount effective toinduce diuresis of a compound of Formula I or II of claim 1 and anantihypertensive agent.
 15. A method according to claim 14 wherein thecompound of Formula I or II used to effect diuresis is a compoundselected from the group consistingof8-chloro-N,N-dimethyl-β,6-diphenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,8-bromo-N,N-dimethyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,8-bromo-N,N-dimethyl-β,6-diphenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,8-chloro-β,6-diphenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,N,N-dimethyl-8-(methylthio)-β,6-diphenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,8-chloro-β-(3-methoxyphenyl)-N,N-dimethyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,8-chloro-β-(2-chlorophenyl)-N,N-dimethyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,8-chloro-N,N,4-trimethyl-β,6-diphenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,8-chloro-β-(4-methoxyphenyl)-N,N-dimethyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,8-iodo-N,N-dimethyl-β,6-diphenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,8-chloro-β-(2-methoxyphenyl)-N,N-dimethyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,8-bromo-N,N-dimethyl-6-(2-pyridinyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-ethanamine,ora pharmacologically acceptable salt thereof.
 16. A method for treatinghypertension in a warm-blooded animal patient which comprisesadministering to said patient an amount effective to lower bloodpressure of a compound of Formula I or II of claim 1.